The present invention relates to medical methods of treatment, pharmaceutical compositions, and use of anti-pressor agents to manufacture such pharmaceutical compositions. More particularly, the present invention concerns the administration of an agent which acts to remodel neuronal or vascular pathways for the long term management of sexual dysfunction in both males and females.
The physiology of an erection or sexual arousal in both the male and female involves central nervous system initiation, neural pathway activation, and vascular smooth muscle relaxation. This signaling mediates vasodilation of the penile, clitoral labial, and vaginal arterial blood vessels and the trabecular meshwork of smooth muscle. The resulting decrease in vascular resistance promotes an increase in arterial inflow and the filling of the corpora cavernosa in the penis and clitoris. Subsequent to there being an appropriate high rate of inflow, the cavernosal xe2x80x9cfillingxe2x80x9d results in occlusion of the sub-tunical veins and full rigidity. The rate of inflow is critical because if there is not enough volume change, venous occlusion can not take place. A selective structurally-based increase in penile resistance produces a substantial impediment to inflow. That is, if penile or clitoral vascular structure, or the vascular structure immediately xe2x80x9cup-streamxe2x80x9d from the genitalia, is more constrained than the rest of the circulation, there would be a xe2x80x9cmismatchingxe2x80x9d of perfusion pressure and selective resistance, i.e. genital arterial insufficiency. On the other hand, it is likely that when hypertension is first established and there is a generalized up-regulation of structurally-based vascular resistance in all vessels, there would not be any deleterious effect on erectile function because of a xe2x80x9cmatchingxe2x80x9d between perfusion pressure and resistance. That is, despite the hypertrophy of the penile vasculature, the arterial pressure is proportionally elevated thereby allowing for adequate blood flow to the penis.
Pathological changes in the genital vasculature and alterations in function control systems have been shown to have a deleterious impact on erectile dysfunction. Local factors such as endothelin and sympathetic nerve mediated release of catecholamines have been shown to be important players in detumescence, but they also are likely to increase trophic responses in this tissue. The physiology of penile and clitoral erection and the structural maintenance of the tissue depends upon a balance between control systems that involve endothelial cells, vascular smooth muscle cells, fibroblasts, extracellular matrix, and nerves. Any shift in the balance of these control systems to either towards trophic responses such as vascular hypertrophy, focal fibrosis, or generalized production of the extracellular matrix or to the extremes of functional control systems can result in erectile dysfunction. Further, as structure and function are so closely related, it is becoming increasingly important in understanding the mechanisms of erectile dysfunction that we investigate the reciprocal impact of structural changes on function and of changes in functional control systems on structure.
The clitoris is the homologue of the penis, arising from the embryological genital tubercle. As a result, the two organs have similar structural and arousal response mechanisms. The clitoris consists of a cylindrical, erectile organ composed of three parts: the outermost glans or head, the middle corpus or body, and the innermost crura. The body of the clitoris consists of paired corpora cavernosa of about 2.5 cm in length and lacks a corpus spongiosum. During sexual arousal, blood flow to the corpora cavernosa of the clitoris cause their enlargement and tumescence.
The clitoris plays a major role during sexual activity in that it contributes to local autonomic and somatic changes causing vaginal vasocongestion, engorgement, and subsequent effects, lubricating the introital canal making the sexual act easier, more comfortable, and more pleasurable.
Vaginal wall engorgement enables a process of plasma transduction to occur, allowing a flow through the epithelium and onto the vaginal surface. Plasma transduction results from the rising pressure in the vaginal capillary bed during the sexual arousal state. In addition, there is an increase in vaginal length and lumenal diameter, especially in the distal 2/3 of the vaginal canal.
It has been well established that the generation of a penile and clitoral erections and vaginal and labial engorgement are greatly dependent on adequate blood flow to vascular beds which feed these organs. Both smooth muscle relaxation of the corpora cavernosa as well as the vasodilation of genital arterial vessels mediate the physiological response. One of the major fundamental etiologies of erectile dysfunction is, thus, inadequate genital arterial inflow. If there is an inappropriate structural narrowing in the supporting vasculature that is not associated with an increase in perfusion pressure, the blood flow into the organs at maximum dilation may be reduced and therefore be insufficient for the generation of an erection. There is increasing recognition that erectile dysfunction, although associated with, may appear prior to the onset of clinical signs of cardiovascular disease and therefore may be an early harbinger of progressing changes.
In both the male and female human, the aorta bifurcates on the fourth lumbar vertebra into the common iliac arteries. The common iliac arteries pass laterally, behind the common iliac veins, to the pelvic brim. At the lower border of the fifth lumbar vertebra, the common iliac arteries divide into internal and external branches. The internal iliac artery supplies blood to all of the organs within the pelvis and send branches through the greater sciatic notch to supply the gluteal muscles and perineum. After passing over the pelvic brim, the internal iliac artery divides into anterior and posterior trunks.
The anterior trunk of the internal iliac artery branches into the superior vesical artery, the inferior vesical artery, the middle rectal artery, the uterine artery, the obturator artery, the internal pudendal artery, and the inferior gluteal artery. The internal pudendal artery supplies blood to the perineum. The artery passes out of the pelvis around the spine of the ischium and back on the inside surface of the ischeal tuberosity and inferior ramus to lie in the pudendal canal. The branches from the internal pudendal artery are the inferior rectal artery which supplies the anal sphincter, skin and lower rectum; the perineal artery which supplies the scrotum in the male and the labia in the female; the artery of the bulb which supplies erectile tissue, the deep dorsal arteries of the penis or deep artery of the clitoris.
It has been demonstrated in several forms of experimental hypertension that xe2x80x9cslow pressor mechanismsxe2x80x9d such as hypertrophic structural changes in the vasculature can almost completely account for the long-term resistance changes associated with the elevated arterial pressure. Based on Poiseuille""s law, it has been shown that vascular resistance in an intact vascular bed is a function of the overall hemodynamic effect of all lumen radii, the number of blood vessels, the length of the vessels and the blood viscosity. In hypertension, increased vascular resistance is most potently conferred by a structurally-based decrease in the radius of the lumen of arterioles and small arteries and also potentially by arteriolar rarefaction whereby even a small change in the average arteriolar radii throughout a vascular bed has a dramatic influence on the resistance to flow. Further, it has been demonstrated that such structural changes can precede the onset of hypertension and therefore may be an initiating mechanism.
Vascular beds in which there is chronic diminished blood flow suffer a degree of pathogenic vascular degradative modeling over time in response to static or circulatory hypoxia. That is, as a normal reaction to diminished blood flow, the lumen in these arteries diminishes in diameter over time, causing decreased blood flow and/or higher pressure during periods of peak blood flow. Those portions of the ilio-hypogastric-pudendal arterial bed which directly feed blood to the sex organs are examples of such less frequently used arterial beds. Because incidents of major blood inflow to the sexual organs are less frequent than to most other organs, a gradual hypoxic response is seen over time in the vasculature directly feeding these organs and in the organs themselves. The body has a self-regulating mechanism to combat this pathogenic modeling: it is known, for example, that in the human male there are a number of spontaneous nocturnal erections which occur as a result of the body""s mechanism for combating hypoxia in penile tissue. Nevertheless, the arteries in a normal flaccid penis and the un-enlarged clitoris and labia are constricted. As a result, typical oxygen concentrations in such tissues are closer to venous rather than arterial oxygen levels. Periodic vasodilation of the penis and clitoris increases oxygen levels in these tissues. The higher oxygen levels supplied to tissue in the penis and clitoris, as well as vasodilation itself, shut down adverse metabolic processes such as TGF-b production and pathogenic vascular wall modeling which result in long term tissue damage.
Therefore, it is differential changes in genital vascular resistance that is likely to be a critical issue in erectile function. That is, if such vascular structural changes take place in the genitalia in the absence of hypertension or systemic changes in vessel structure there would not be the increase in arterial pressure required to compensate for the increased resistance. It may be that this condition could occur as an early indicator of progressing cardiovascular disease. The appearance of erectile dysfunction preceding the global clinical signs of hypertension may, in fact, suggest an increased susceptibility of this vascular bed to pathological changes.
In its principal embodiment, the present invention provides a method for the long term management of sexual dysfunction in males and females by administering a therapeutic agent which remodels neuronal or vascular pathways. In a preferred embodiment, the invention provides a method of ameliorating, inhibiting or reversing pathogenic vascular degradative modeling in the ilio-hypogastric-pudendal arterial bed and genitalia comprising administering to a human patient in need of such treatment a therapeutically effective amount of an anti-pressor agent. In one embodiment, the present invention provides the use of an anti-pressor agent for the manufacture of pharmaceutical compositions for ameliorating, inhibiting or reversing pathogenic vascular degradative modeling in the ilio-hypogastric-pudendal arterial bed and genitalia.
The anti-pressor agent is administered chronically at low doses ranging between about one-twentieth to about one-half the dose required to evoke vasodilation in a patient exhibiting normal circulation or, alternatively, is administered over a period of time ranging between about five days to about 21 days at higher doses ranging between about 1.5 to about 3 times the dose required to evoke vasodilation in a patient exhibiting normal circulation.